The objective of this research is to develop new approaches in the design of effective agents for the treatment of cancer. The proposed studies include the synthesis and biochemical and/or biological studies of specific analogs of the folate-cofactor of thymidylate synthetase, new nucleoside and nucleotide analogs, synthetic oligonucleotides and chemically modified tRNAs to act as specific "anti-primer" inhibitors of RNA dependent DNA polymerases, and phosphoraziridines, as "electron-affinic" or "phosphorylating" radiation-sensitizers. Studies of the possible alternative mechanisms of action of the phosphoraziridines will be conducted, using physico-chemical methods. The action of nucleoside and folate analogs, modified oligo- and polynucleotides, and other agents on nucleic acid metabolism, and their immunologic properties will be studied in a primary mouse spleen lymphocyte system.